Download Carboxylic Acid Derivatives and Nucleophilic Acyl Substitution

Chapter 15. Carboxylic
Acid Derivatives
Based on McMurry’s Organic Chemistry, 6th edition
Carboxylic Compounds
 Acyl group bonded to Y, an electronegative atom or leaving
group
 Includes: Y = halide (acid halides), acyloxy (anhydrides), alkoxy
(esters), amine (amides), thiolate (thioesters), phosphate (acyl
phosphates)
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Naming Carboxylic Acid Derivatives
 Acid Halides, RCOX

Derived from the carboxylic acid name by replacing the -ic
acid ending with -yl or the -carboxylic acid ending with –
carbonyl and specifying the halide
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Naming Acid Anhydrides, RCO2COR'
 If symmetrical replace “acid” with “anhydride” based on the
related carboxylic acid (for symmetrical anhydrides)
 From substituted monocarboxylic acids: use bis- ahead of the
acid name
 Unsymmetrical anhydrides— cite the two acids alphabetically
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Naming Amides, RCONH2
 With unsubstituted NH2 group. replace -oic acid or -ic acid
with -amide, or by replacing the -carboxylic acid ending with –
carboxamide
 If the N is further substituted, identify the substituent groups
(preceded by “N”) and then the parent amide
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Naming Esters, RCO2R
 Name R’ and then, after a space, the carboxylic acid (RCOOH),
with the “-ic acid” ending replaced by “-ate”
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Nomenclature review
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Nucleophilic Acyl Substitution
 Carboxylic acid derivatives have an acyl carbon bonded to a
group Y that can leave
 A tetrahedral intermediate is formed and the leaving group is
expelled to generate a new carbonyl compound, leading to
substitution
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Nucleophilic Acyl Substitution:
General Reaction Pattern
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Relative Reactivity of Carboxylic Acid Derivatives
 Nucleophiles react more
readily with unhindered
carbonyl groups
 More electrophilic
carbonyl groups are more
reactive to addition (acyl
halides are most reactive,
amides are least)
 The intermediate with the
best leaving group
decomposes fastest
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Substitution in Synthesis
 We can readily convert a more reactive acid derivative into a
less reactive one
 Reactions in the opposite sense are possible but require more
complex approaches
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General Reactions of Carboxylic Acid Derivatives
 water
carboxylic acid
 alcohols
esters
 ammonia or an amine
an amide
 hydride source
an
aldehyde or an alcohol
 Grignard reagent
a
ketone or an alcohol
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Mechanism of the Fischer Esterification
 The reaction is an acid-catalyzed, nucleophilic acyl substitution
of a carboxylic acid
 When 18O-labeled methanol reacts with benzoic acid, the methyl
benzoate produced is 18O-labeled but the water produced is
unlabeled
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Conversion of Carboxylic Acids into Acid Chlorides
 Reaction with thionyl chloride, SOCl2
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Chemistry of Acid Halides
 Acid chlorides are prepared from carboxylic acids by reaction
with SOCl2
 Reaction of a carboxylic acid with PBr3 yields the acid bromide
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Reactions of Acid Halides




Nucleophilic acyl substitution
Halogen replaced by OH, by OR, or by NH2
Reduction yields a primary alcohol
Grignard reagent yields a tertiary alcohol
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Hydrolysis: Conversion of Acid Halides into Acids
 Acid chlorides react with water to yield carboxylic acids
 HCl is generated during the hydrolysis: a base is added to
remove the HCl
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Conversion of Acid Halides into Esters
 Esters are produced in the reaction of acid chlorides with
alcohols in the presence of pyridine or NaOH
 The reaction is better with less steric bulk
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Aminolysis: Conversion of Acid Halides into Amides
 Amides result from the reaction of acid chlorides with NH3,
primary (RNH2) and secondary amines (R2NH)
 The reaction with tertiary amines (R3N) gives an unstable
species that cannot be isolated
 HCl is neutralized by the amine or an added base
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Chemistry of Esters
 Many esters are pleasant-smelling liquids: fragrant odors of
fruits and flowers
 Also present in fats and vegetable oils
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Preparation of Esters
 Esters are usually prepared from carboxylic acids
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Reactions of Esters
 Less reactive toward nucleophiles than are acid chlorides or
anhydrides
 Cyclic esters are called lactones and react similarly to acyclic
esters
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Hydrolysis:
Conversion of Esters into Carboxylic Acids
 An ester is hydrolyzed by aqueous base or aqueous acid to
yield a carboxylic acid plus an alcohol
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Mechanism of Base Catalyzed Ester Hydrolysis
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Acid Catalyzed Ester Hydrolysis
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Reduction: Conversion of Esters into Alcohols
 Reaction with LiAlH4 yields primary alcohols
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Chemistry of Amides
 Prepared by reaction of an acid chloride with ammonia,
monosubstituted amines, or disubstituted amines
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Reactions of Amides
 Heating in either aqueous acid or aqueous base produces a
carboxylic acid and amine

Acidic hydrolysis by nucleophilic addition of water to the
protonated amide, followed by loss of ammonia
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Basic Hydrolysis of Amides
 Addition of hydroxide and loss of amide ion
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Reduction: Conversion of Amides into Amines
 Reduced by LiAlH4 to an amine rather than an alcohol
 Converts C=O  CH2
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Uses of Reduction of Amides
 Works with cyclic and acyclic
 Good route to cyclic amines
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End of chapter 15
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